HUMAN NEUROSCIENCEPERSPECTIVE ARTICLE

published: 04 July 2014doi: 10.3389/fnhum.2014.00498

Revisiting the continuum hypothesis: toward an in-depthexploration of executive functions in Korsakoff syndromeMélanie Brion1, Anne-Lise Pitel 2, Hélène Beaunieux 2 and Pierre Maurage1*1 Laboratory for Experimental Psychopathology, Institute of Psychology, Université Catholique de Louvain, Louvain-la-Neuve, Belgium2 INSERM, École Pratique des Hautes Études, Université de Caen-Basse Normandie, Unité U1077, GIP Cyceron, CHU Caen, Caen, France

Edited by:Anneke E. Goudriaan, Arkin Institutefor Mental Health, Netherlands

Reviewed by:Esther Fujiwara, University of Alberta,CanadaMichael David Kopelman, King’sCollege London, UK

*Correspondence:Pierre Maurage, Laboratoire dePsychopathologie Expérimentale,Faculté de Psychologie, UniversitéCatholique de Louvain, 10 Place C.Mercier, Louvain-la-Neuve B-1348,Belgiume-mail: pierre.maurage@uclouvain.be

Korsakoff syndrome (KS) is a neurological state mostly caused by alcohol-dependence andleading to disproportionate episodic memory deficits. KS patients present more severeanterograde amnesia than Alcohol-Dependent Subjects (ADS), which led to the continuumhypothesis postulating a progressive increase in brain and cognitive damages during theevolution from ADS to KS.This hypothesis has been extensively examined for memory butis still debated for other abilities, notably executive functions (EF). EF have up to now beenexplored by unspecific tasks in KS, and few studies explored their interactions with mem-ory. Exploring EF in KS by specific tasks based on current EF models could thus renewthe exploration of the continuum hypothesis. This paper will propose a research programaiming at: (1) clarifying the extent of executive dysfunctions in KS by tasks focusing onspecific EF subcomponents; (2) determining the differential EF deficits in ADS and KS; (3)exploring EF-memory interactions in KS with innovative tasks. At the fundamental level,this exploration will test the continuum hypothesis beyond memory. At the clinical level, itwill propose new rehabilitation tools focusing on the EF specifically impaired in KS.

Keywords: alcohol-dependence, executive functions, inhibition, Korsakoff syndrome

INTRODUCTIONThe negative consequences of chronic excessive alcohol consump-tion on health are well established, alcohol-dependent subjects(ADS) presenting impairments in several body systems (Rehmet al., 2009; Bühler and Mann, 2011). Alcohol misuse can alsolead to nutritional problems increasing the risk of thiamine defi-ciency (Victor et al., 1971; Lough, 2012). Repeated thiaminedeprivation can provoke cerebral disorders such as the Wernicke’sencephalopathy, a medical emergency with lethal risk (Thom-son and Marshall, 2006) potentially progressing toward Korsakoffsyndrome (KS). KS is a neurological complication of alcohol-dependence (Victor et al., 1971; Isenberg-Grzeda et al., 2012)combining alcohol neurotoxicity and thiamine deficiency (Brand,2007; Pitel et al., 2008; Fama et al., 2012). The cardinal KS symp-tom is a permanent anterograde and retrograde amnesia, whichhas been widely explored. However, other cognitive impairmentsrelated to KS, and notably executive functions (EF) known to behighly impaired in alcohol-dependence, have been less explored.

After reviewing earlier neuropsychological explorations of KS,this paper will underline the importance of further exploring EFin this pathology. A research program will be proposed, with threecrucial aims: (1) clarifying the extent of executive dysfunctions inKS; (2) determining the differential deficits across specific EF inADS and KS; (3) exploring the interactions between EF and mem-ory impairments in KS. This thorough exploration might lead toa new model of cognitive impairments in KS, which will havecrucial implications at fundamental (i.e., revaluation of the con-tinuum hypothesis proposing the continuity in the impairmentsbetween ADS and KS) and clinical (i.e., new neuropsychologicalrehabilitation perspectives) levels.

WHAT DO WE KNOW ABOUT MEMORY DEFICITS IN KS?Severe retrograde and anterograde amnesia is the most exploredsymptom in KS (Brand et al., 2009; Fama et al., 2012; Kesselsand Kopelman, 2012; Pitel et al., 2012; Sullivan and Fama, 2012).Indeed, thiamine deficiency affects diencephalic and limbic struc-tures (Borsutzky et al., 2008; Labudda et al., 2008; Brand et al.,2009), leading to episodic memory disorders (Pitel et al., 2011).KS notably present abnormalities in the hippocampi, mammil-lary bodies, and thalamic nuclei (Pitel et al., 2012), these regionsbeing involved in episodic memory (Brand et al., 2009; Harper,2009; Kopelman et al., 2009; Sullivan and Pfefferbaum, 2009;Kril and Harper, 2012). Episodic memory is a long-term mem-ory subcomponent gathering features related to specific events,situations, and experiences, and involving the encoding, storage,and retrieval of the event and its spatio-temporal context (Tul-ving, 2001). Episodic memory system also encompass autonoeticconsciousness, the ability to time traveling into one’s own recollec-tions (Wheeler et al., 1997). Therefore, many studies (Brand, 2007;d’Ydewalle and Van Damme, 2007; Pitel et al., 2008) separatelyinvestigated each episodic memory components and confirmedthat KS have deficits for episodic encoding and retrieval, impairedcontextual memory, and altered autonoetic consciousness. There-fore, KS clearly present lower performance than controls and AD inepisodic memory, this impairment being associated with reducedthalamic and frontal volumes (Shimamura et al., 1988).

Other memory systems are also impaired in KS, particularly: (1)autobiographical memory, including general knowledge, seman-tic information, and personal events (Race and Verfaellie, 2012);(2) implicit learning, tested with motor (Hayes et al., 2012), andcognitive (Beaunieux et al., 2013) skill learning. Conversely, the

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working memory slave systems (i.e., phonological loop and visu-ospatial sketchpad; Baddeley et al., 1996) involved in the encodingphase (Van Geldorp et al., 2012) appear relatively preserved in KS(Pitel et al., 2008).

Beside memory systems, abilities simultaneously involvingmemory and other cognitive functions have also been partly inves-tigated. Confabulations, namely unintentional and incongruousverbal production (Dalla Barba and Decaix, 2009; Kessels andKopelman, 2012) have been described in KS (Borsutzky et al.,2008; Bouzerda-Wahlen et al., 2013) and are usually interpreted asrelated to memory dysfunction. However, while involving mem-ory, they might also be related to other cognitive abilities, notablyEF (Metcalf et al., 2007). Indeed, spontaneous confabulations the-ories emphasized the role of frontal cortices and EF dysfunctionin their occurrence (Metcalf et al., 2007; Dalla Barba and Decaix,2009). Other cognitive abilities simultaneously involving memoryand EF have also been explored, particularly: (1) metamemory,impaired in ADS (Le Berre et al., 2010) and modulated by EFimpairments; (2) cognitive procedural learning, altered in KS andADS (Beaunieux et al., 2013) and also relying on EF. The memoryimpairments described in KS thus seem to be at least partly relatedto EF impairments.

WHAT DO WE KNOW ABOUT EXECUTIVE FUNCTIONINGIN KS?Beyond memory, the description of executive impairments in KSled to the proposal that KS should be reconsidered as a frontal lobepathology (Van Oort and Kessels, 2009; Jung et al., 2012; Oscar-Berman, 2012; Maharasingam et al., 2013). Frontal lobes are cru-cial for EF and, as they are highly vulnerable to alcohol neurotoxic-ity (Moselhy Hamdy, 2001; Reed et al., 2003; Oscar-Berman, 2012;Pitel et al., 2012; Maharasingam et al., 2013), alcohol-dependenceleads to largely explored EF deficits (Stavro et al., 2013). EF impair-ments have also been explored in KS, but their understandingshould be renewed as EF contribution to amnesia remains debated(Kessels and Kopelman, 2012; Oscar-Berman, 2012).

Two contradictory proposals indeed exist. First, as alcohol neu-rotoxicity mostly affects frontal lobes (Fujiwara et al., 2008) whilethiamine deficiency affects diencephalic regions (Jacobson andLishman, 1990; Brokate et al., 2003; Brand, 2007; Fama et al.,2012), ADS, and KS might be characterized by similar EF impair-ments (due to alcohol effects on frontal regions), the differencebeing found for memory (increased in KS due to thiamine defi-ciency). Neuropsychological investigations indeed showed parallelEF impairments in ADS and KS, with more severe episodic mem-ory deficits in KS (Pitel et al., 2008). Second and conversely, thecontinuum hypothesis (Butters and Brandt, 1985; Pitel et al., 2008;Sullivan and Pfefferbaum, 2009) postulates continuity in cognitiveimpairments between ADS and KS, KS being centrally character-ized by a global worsening of alcohol-dependence deficits whichcannot be fully accounted by differences in drinking history (Pitelet al., 2008), contrary to early statements (Ryback, 1971). KS wouldthus present stronger deficits than ADS for memory, but also forEF (Oscar-Berman et al., 2004; Jung et al., 2012). However, whileEF have been studied in KS, most studies focus on memory and theexploration of EF deficits in KS should be deepened. In short, it isnow accepted that KS have disproportionate memory impairment

across episodic memory tasks whereas there is no clear-cut opin-ion about (dis)continuity between ADS and KS for other cognitivefunctions. There is thus insufficient evidence to determine whetherthere is a continuum of EF impairment from ADS to KS.

Studies that investigated EF in KS used a wide variety ofunspecific tasks simultaneously tapping into different EF with-out being theoretically grounded. An inventory of EF tasks usedin KS is presented in Figure 1A. Studies were classified accordingto Miyake et al. (2000) categorization. Indeed, while EF organi-zation remains questionable (Fournier-Vicente et al., 2008; Hullet al., 2008; Adrover-Roig et al., 2012), this multi-factorial modelclearly subdivides EF into three basic factors, to which two com-plex factors were recently added (Fournier-Vicente et al., 2008;Adrover-Roig et al., 2012): (1) shifting, the ability to transfer cog-nitive resources across tasks; (2) updating, the ability to replaceirrelevant information by pertinent new ones; (3) inhibition, thecontrol ability preventing a non-pertinent automatic or dominantresponse to occur; (4) planning, the self-regulation based on astrategic elaboration of the successive stages in non-routine situ-ations; (5) long-term memory strategic retrieval, the selection ofcorrect information in memory.

As shown in Figure 1, early findings (e.g., Janowsky et al.,1989; Kopelman, 1991) showed that KS cognitive deficits are partlyattributable to frontal lobe dysfunctions. A comparison betweenAlzheimer and KS patients (Kopelman, 1991) clearly illustrated thepresence of frontal impairment in KS and its influence on retro-grade amnesia. A comparison between patients with frontal lesion,amnesia, and KS also demonstrated that frontal lobe damage is aspecific cognitive pattern for KS compared to other types of amne-sia (Janowsky et al., 1989). More recent findings demonstrated thatEF are globally impaired in KS, KS patients performing poorly onshifting (Brokate et al., 2003; Fama et al., 2004), updating (Hilde-brandt et al., 2004; Pitel et al., 2008), and inhibition (Fujiwaraet al., 2008; Pitel et al., 2008). KS appears mostly associated withdisinhibition, high interference sensitivity, poor judgment, andplanning abilities, problem solving inabilities, and perseverativeresponses (Oscar-Berman, 2012). Moreover, explorations testingglobal dysexecutive symptoms (Van Oort and Kessels, 2009; Maha-rasingam et al., 2013) showed higher impairments in KS thanADS. However, very few studies directly compared ADS and KSperformances (e.g., Brokate et al., 2003; Hildebrandt et al., 2004;Oscar-Berman et al., 2004; Pitel et al., 2008) and these investiga-tions used tasks simultaneously involving several EF. Moreover, aseach study focused on a limited range of tasks, the current data donot offer a comparison of the deficit across EF.

WHAT DO WE KNOW ABOUT EF-MEMORY INTERACTIONS INKS?Memory impairments are the key feature in KS, but their inter-actions with other cognitive functions are less explored. However,frontal lobes and EF play a critical role in memory performance,as illustrated by the prefrontal cortex involvement in memory(Habib et al., 2003; Salthouse et al., 2003; Parks et al., 2011; Kimet al., 2013). In the last three decades, there have been variousattempts to establish reliable measures of EF among KS patientsto understand their relation with memory (Squire, 1982; Leng andParkin, 1988; Kopelman, 1991; Brokate et al., 2003). For example,

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FIGURE 1 | (A) Overview of multifaceted tasks previously used for EFassessment in KS. Tasks are classified according to their central EFsubcomponent. Color rectangles at the right of each task underline theother EF subcomponents involved in this task. Purple rectangles

indicate the overlap between EF subcomponents and problem solving (acomplex and transversal EF involved in several tasks). (B) Overview ofthe EF assessment program proposed by Miyake et al. (2000) andFriedman and Miyake (2004).

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by using a wide-range of frontal and memory tasks, Kopelman(1991) established an influence of frontal deficits on retrogradememory processes. In the same line, KS and post-encephaliticamnesic patients’ performance on WCST and Cognitive Estima-tion Test (CET) were compared (Leng and Parkin, 1988; Shoqeiratet al., 1990), showing a double dissociation for frontal dysfunction(i.e., impaired WCST but preserved CET performance for KS, andthe reverse pattern for post-encephalitic amnesic patients). Theseresults suggest that there are different patterns of frontal dysfunc-tion that could be involved in memory deficit. More recently, somestudies in KS confirmed that EF impairment is involved in memorydeficits (Fama et al., 2004; Oscar-Berman, 2012). However, theseprevious studies were based on a correlational approach using sep-arate explorations of EF and memory impairments, and not on thedirect exploration of their interactions.

Interactions between EF and memory could also be illustratedby the context memory deficit hypothesis (Schnider et al., 1996)underlining the role of context memory impairment in amnesia.Indeed, KS patients are unable to remember background con-text such as spatio-temporal or intrinsic context (Borsutzky et al.,2008). In this view, context is regarded as “extra information” thatcan cue memory retrieval (Metcalf et al., 2007). Several studies(e.g., Kessels and Kopelman, 2012) have emphasized the relationbetween frontal lobe damage and contextual memory impair-ments, and disorientation-confabulation might follow memoryand EF dysfunctions (Bouzerda-Wahlen et al., 2013). Therefore,the presence of spontaneous confabulation in KS arises from acombination of amnesia and frontal lobe dysfunctions (Kopel-man, 1987). Although EF dysfunction is not univocally linked tofrontal lobe damage, the crucial involvement of frontal regionsin efficient executive abilities has been largely established dur-ing the last decades (Scott and Schoenberg, 2011). Frontal lobedamage might thus lead to executive control failure, which mightimpair the identification of events’ temporal context, those factorsleading to repetitive confabulations (Kessels and Kopelman, 2012;Oscar-Berman, 2012). Centrally, spontaneous confabulations canbe observed in KS (Borsutzky et al., 2008), resulting from strate-gic retrieval impairment, which results from executive dysfunc-tion as they lead to search failure and wrong memories selection(Burgess and Shallice, 1996; Metcalf et al., 2007). Frontal lobesare thus clearly involved in spontaneous confabulations (Kopel-man et al., 2009), which is further reinforced by neuroimagingstudies showing that they are related to damage in ventro-medialand/or orbito-frontal regions (Kopelman et al., 2009). Indeed,while orbito-frontal damage does not necessarily result in EF dys-functions, this area clearly belongs to a neural network involved inexecutive functioning (Szatkowska et al., 2007).

WHAT SHOULD BE DONE IN FUTURE STUDIES?A large literature has been developed on executive dysfunction inADS (Stavro et al., 2013), notably showing the impact of execu-tive dysfunctions on relapse (Bickel et al., 2012). Besides, studieson ADS investigated EF and their interactions with memory byusing purer tests dedicated to one particular EF. For instance,ADS impairments in inhibition, shifting, and attentional bias foralcohol-related cues were observed during a go/no-go task (linkedto inhibition performance) with neutral and alcohol-related words

(Noël et al., 2005). Also, EF assessment (Fluency tasks, Stroop task,and n-back paradigm) revealed that performance on fluency taskwas a significant predictor of learning abilities (Spondee task, Pitelet al., 2007a). These results clearly demonstrate the implication ofEF in some memory processes.

However, an accurate overview of executive functioning com-paring ADS and KS cannot be established so far due to the lack ofdata and the use of composite executive tasks. Owing to the multi-faceted nature of the EF tasks, it is hard to specify the contributionof each of Miyake’s factors (Shifting, Updating, and Inhibition)to some classic and/or complex tests routinely used to assess EF(Friedman and Miyake, 2004). The traditional EF tasks used forneuropsychological assessment are composite, resulting in a diffi-culty to investigate the continuum hypothesis for each EF. Theflowchart in Figure 1A shows the EF overlap on certain tasksand underlines that most tests assessing EF in KS are multifac-eted. Beside, since KS can be associated with varying nosologicalterms (i.e., ADS studies might have included a proportion ofpatients with undetected KS), an issue arises as to whether neu-ropsychological findings reflect various experimental design ordifferences in sample selection (Squire, 1982; Bowden, 1990). Thisperspective promote the importance of updating past neuropsy-chological findings (e.g., Leng and Parkin, 1988; Janowsky et al.,1989; Kopelman, 1991) on the relation between frontal dysfunc-tion and memory impairment with a new experimental designprogram that includes a direct comparison between ADS and KS.

On the basis of studies presented above and questions held inabeyance, the possible line of approach for future studies will nowbe described by showing how EF may constitute a relevant researchfocus in the exploration of memory deficits in KS. This researchapproach is summarized in Figure 1B. Centrally, three researchaxes are proposed:

(1) Using specific EF tasks: future studies should use tasks eval-uating each basic EF components (updating, shifting, andinhibition), e.g., the nine Miyake’s tasks (Miyake et al., 2000;see Figure 1B) which have been found to specifically explorethe distinct EF subcomponents. The validity of these tasks hasbeen reinforced by studies confirming the underlying multi-factorial model of EF in various healthy samples (Heddenand Yoon, 2006; Vaughan and Giovanello, 2010; Zheng et al.,2014). Although Miyake’s tasks have not yet been applied topsychiatric population, they are now widely used to explore EF(Fournier-Vicente et al., 2008) and present higher sensitivityand lower ceiling effect than classical EF tasks. In addition, apurer alternative to classic multifaceted planning tasks mightbe the unstructured task (Kramer et al., 2013) modeled afterthe six-elements test (Shallice and Burgess, 1991). This sys-tematic exploration of EF subcomponents will clarify thedifferential deficit across EF in KS, identifying impaired andpotentially preserved subcomponents.

(2) Systematically comparing ADS and KS: exploring and com-paring thoroughly EF in KS,ADS, and healthy participants willstep up the actual knowledge on this topic. Besides the ninetasks presented above, a specific exploration of inhibition sub-component might be proposed (Friedman and Miyake, 2004;see Figure 1B), inhibition being classically considered as the

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central EF in addiction. This thorough comparison betweenADS and KS will allow a direct testing of the validity of thecontinuum hypothesis in EF. It might indeed be postulatedthat the validity of this hypothesis varies across EF, a contin-uum being found for several EF subcomponents but not forothers. In view of the massive inhibition impairments earlierobserved in KS (Fujiwara et al., 2008; Pitel et al., 2008), it canbe hypothesized that inhibition subcomponent will show agradual decline from ADS to KS, a continuum not necessarilyobserved for other EF.

(3) Directly testing EF-memory interactions: the interactionbetween basic executive factors and retrieval memory processshould be directly tested among KS and ADS. The Stop-Signal Task could be tailored to include a learning aspectbased on classic memory learning task (e.g., California Ver-bal Learning Test; Elwood, 1995). Indeed, the Stop-SignalTask consists in two blocks of trials. During the first trial,participants have to perform a simple binary categorizationtask on words. Instructions for the second block are identicalbut participants have to inhibit their answer when hearing asound after the word appearance. The modified Stop-SignalTask would include a preliminary block in which partici-pants have to remember a list of words that will serve forthe categorization (i.e., learned and non-learned words) insuch a way that both inhibition and memory retrieval couldbe manipulated in the same task (i.e., inhibiting the prepotentresponse to the stop-signal while discriminating words). Con-trary to classical approach (e.g., Shoqeirat et al., 1990) com-paring results for separate memory and EF tasks, this methodwill simultaneously manipulate the two processes (inhibitionand memory retrieval) in the same task to directly observetheir interactions. More globally, the EF-memory interactionsshould be explored by innovative tasks combining specific EFsubcomponent and memory demands.

To conclude, this perspective paper underlined the usefulnessof developing more specific tasks to explore EF in KS. At the fun-damental level, comparing ADS and KS performances with theabove-mentioned tasks would clarify the debate on the contin-uum hypothesis by determining its validity for each EF and forEF-memory interactions. At the clinical level, a straightforwardexamination of EF process would identify the differential deficitsin KS and lead to specific rehabilitation proposals already appliedin ADS, e.g., cognitive enhancement (Sofuoglu et al., 2013) orinhibition training (Houben et al., 2011).

ACKNOWLEDGMENTSPierre Maurage (Research Associate) is founded by the BelgianFund for Scientific Research (F.N.R.S., Belgium).

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Conflict of Interest Statement: The authors declare that the research was conductedin the absence of any commercial or financial relationships that could be construedas a potential conflict of interest.

Received: 05 February 2014; accepted: 19 June 2014; published online: 04 July 2014.Citation: Brion M, Pitel A-L, Beaunieux H and Maurage P (2014) Revisiting the con-tinuum hypothesis: toward an in-depth exploration of executive functions in Korsakoffsyndrome. Front. Hum. Neurosci. 8:498. doi: 10.3389/fnhum.2014.00498This article was submitted to the journal Frontiers in Human Neuroscience.Copyright © 2014 Brion, Pitel, Beaunieux and Maurage. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided the originalauthor(s) or licensor are credited and that the original publication in this journal is cited,in accordance with accepted academic practice. No use, distribution or reproduction ispermitted which does not comply with these terms.

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